Similar Datasets
Project description:Mammalian pregnancy depends on the ability of the uterus to support embryo implantation. Previous studies reveal the Sox17 gene as a downstream target of the Pgr-Gata2-dependent transcription network that directs genomic actions in the uterine endometrium receptive for embryo implantation. Here, we report that ablating Sox17 in the uterine epithelium impairs leukemia inhibitory factor (LIF) and Indian hedgehog homolog (IHH) signaling, leading to failure of embryo implantation. In vivo deletion of the SOX17-binding region 19?kb upstream of the Ihh locus by CRISPR-Cas technology reduces Ihh expression specifically in the uterus and alters proper endometrial epithelial-stromal interactions, thereby impairing pregnancy. This SOX17-binding interval is also bound by GATA2, FOXA2, and PGR. This cluster of transcription factor binding is common in 737 uterine genes and may represent a key regulatory element essential for uterine epithelial gene expression.
| S-EPMC6200785 | biostudies-literature
Project description:Mammalian embryo development is dependent on the ability of the uterus to allow and support the implantation of the embryo. Here we demonstrate that ablation of Sox17 specifically in the uterine epithelium results in altered uterine epithelial cell proliferation, uterine gland development and embryo implantation. Uteri lacking Sox17 showed reduction in LIF and IHH signaling which are critical for embryo implantation. ChIP-seq analysis demonstrated that SOX17 binds to a region 19kb 5’ to the Ihh locus. In vivo deletion of this enhancer by the CRISPR-Cas technology reduced Ihh expression in uteri and altered proper endometrial epithelial-stromal interactions required for pregnancy leading to compromised fertility. The SOX17 binding peak at 19kb from the Ihh promoter also bound GATA2, FOXA2 and PGR. Bioinformatic analysis of regions overlapping SOX17, GATA2, FOXA2 and PGR bindings shows 737 genes with these common binding sites. This cluster of transcription factors identified in this enhancer region may represent a combination of regulatory elements essential for uterine epithelial gene expression and differentiation.
2018-08-09 | GSE118264 | GEO
Project description:Mammalian embryo development is dependent on the ability of the uterus to allow and support the implantation of the embryo. Here we demonstrate that ablation of Sox17 specifically in the uterine epithelium results in altered uterine epithelial cell proliferation, uterine gland development and embryo implantation. Uteri lacking Sox17 showed reduction in LIF and IHH signaling which are critical for embryo implantation. ChIP-seq analysis demonstrated that SOX17 binds to a region 19kb 5’ to the Ihh locus. In vivo deletion of this enhancer by the CRISPR-Cas technology reduced Ihh expression in uteri and altered proper endometrial epithelial-stromal interactions required for pregnancy leading to compromised fertility. The SOX17 binding peak at 19kb from the Ihh promoter also bound GATA2, FOXA2 and PGR. Bioinformatic analysis of regions overlapping SOX17, GATA2, FOXA2 and PGR bindings shows 737 genes with these common binding sites. This cluster of transcription factors identified in this enhancer region may represent a combination of regulatory elements essential for uterine epithelial gene expression and differentiation.
2018-08-09 | GSE118327 | GEO
Project description:SOX17 regulates uterine epithelial-stromal crosstalk acting via a distal enhancer upstream of Ihh
| PRJNA485189 | ENA
Project description:SOX17 regulates uterine epithelial-stromal crosstalk acting via a distal enhancer upstream of Ihh [array]
| PRJNA484976 | ENA
Project description:SOX17 regulates uterine epithelial-stromal crosstalk acting via a distal enhancer upstream of Ihh [ChIP-seq]
| PRJNA485190 | ENA
Project description:Embryo implantation is regulated by a variety of endometrial factors, including cytokines, growth factors, and transcription factors. Earlier studies identified the leukemia inhibitory factor (LIF), a cytokine produced by uterine glands, as an essential regulator of implantation. LIF, acting via its cell surface receptor, activates the signal transducer and activator of transcription 3 (STAT3) in the uterine epithelial cells. However, the precise mechanism via which activated STAT3 promotes uterine function during implantation remains unknown. To identify the molecular pathways regulated by STAT3, we created SW(d/d) mice in which Stat3 gene is conditionally inactivated in uterine epithelium. The SW(d/d) mice are infertile due to a lack of embryo attachment to the uterine luminal epithelium and consequent implantation failure. Gene expression profiling of uterine epithelial cells of SW(d/d) mice revealed dysregulated expression of specific components of junctional complexes, including E-cadherin, ?- and ?-catenin, and several claudins, which critically regulate epithelial junctional integrity and embryo attachment. In addition, uteri of SW(d/d) mice exhibited markedly reduced stromal proliferation and differentiation, indicating that epithelial STAT3 controls stromal function via a paracrine mechanism. The stromal defect arose from a drastic reduction in the production of several members of the epidermal growth factor family in luminal epithelium of SW(d/d) uteri and the resulting lack of activation of epidermal growth factor receptor signaling and mitotic activity in the stromal cells. Collectively, our results uncovered an intricate molecular network operating downstream of STAT3 that regulates uterine epithelial junctional reorganization, and stromal proliferation, and differentiation, which are critical determinants of successful implantation.
| S-EPMC3857199 | biostudies-literature
Project description:In peripheral nerves, large caliber axons are ensheathed by myelin-elaborating Schwann cells. Multiple lines of evidence demonstrate that expression of the genes encoding myelin structural proteins occurs in Schwann cells in response to axonal instructions. To gain further insight into the mechanisms controlling myelin gene expression, we used reporter constructs in transgenic mice to search for the DNA elements that regulate the myelin basic protein (MBP) gene. Through this in vivo investigation, we provide evidence for the participation of multiple, widely distributed, positive and negative elements in the overall control of MBP expression. Notably, all constructs bearing a 0.6 kb far-upstream sequence, designated Schwann cell enhancer 1 (SCE1), expressed at high levels in myelin-forming Schwann cells. In addition, robust targeting activity conferred by SCE1 was shown to be independent of other MBP 5' flanking sequence. These observations suggest that SCE1 will make available a powerful tool to drive transgene expression in myelinating Schwann cells and that a focused analysis of the SCE1 sequence will lead to the identification of transcription factor binding sites that positively regulate MBP expression.
| S-EPMC6762685 | biostudies-literature
Project description:Little is known regarding how steroid hormone exposures impact the epigenetic landscape in a living organism. Here, we took a global approach to understanding how exposure to the estrogenic chemical, diethylstilbestrol (DES), affects the neonatal mouse uterine epigenome. Integration of RNA- and ChIP-sequencing data demonstrated that ?80% of DES-altered genes had higher H3K4me1/H3K27ac signal in close proximity. Active enhancers, of which ?3% were super-enhancers, had a high density of estrogen receptor alpha (ER?) binding sites and were correlated with alterations in nearby gene expression. Conditional uterine deletion of ER?, but not the pioneer transcription factors FOXA2 or FOXO1, prevented the majority of DES-mediated changes in gene expression and H3K27ac signal at target enhancers. An ER? dependent super-enhancer was located at the Padi gene locus and a topological connection to the Padi1 TSS was documented using 3C-PCR. Chromosome looping at this site was independent of ER? and DES exposure, indicating that the interaction is established prior to ligand signaling. However, enrichment of H3K27ac and transcriptional activation at this locus was both DES and ER?-dependent. These data suggest that DES alters uterine development and consequently adult reproductive function by modifying the enhancer landscape at ER? binding sites near estrogen-regulated genes.
| S-EPMC6009594 | biostudies-literature
Project description:The yin and yang of female fertility is a complicated issue; large numbers of women/couples desire fertility and seek assisted reproduction intervention to achieve conception, while others seek to prevent pregnancy. Understanding specific molecules which control endometrial-embryo interactions is essential for both facilitating and preventing pregnancy. SOX17 has recently emerged as an important transcription factor involved in endometrial receptivity and embryo implantation. However, studies to date have examined mouse models of pregnancy which do not necessarily translate to the human. Demonstration of a role for 'implantation factors' in a human system is critical to provide a rationale for in depth clinical investigation and targeting of such factors. We demonstrate that SOX17is present within the receptive human endometrium and is up-regulated within human endometrial epithelial cells by combined estrogen & progesterone, the hormonal milieu during the receptive window. SOX17 localizes to the point of adhesive contact between human endometrial epithelial cells and a human 'embryo mimic' model (trophectodermal spheroid). Targeting SOX17 in endometrial epithelial cells using CRISPR/Cas9 knockdown or a SOX-F family inhibitor, MCC177, significantly inhibited adhesion of an trophectodermal spheroids to the epithelial cells thereby preventing 'implantation'. These data confirm the important role of endometrial SOX17 in human endometrial receptivity and embryo implantation.
| S-EPMC6820561 | biostudies-literature